M. M. Fomina

Metal polyacrylates, ferrocene derivatives, and polysuccinimide as potential antitumor drugs

Compounds belonging to three novel groups of oncological drugs (metal polyacrylates, ferrocene derivatives, and polysuccinimide) showed antitumor activity. The most efficient compounds, viz., gold polyacrylate (auracryl), 2-[(1-ferrocenylethyl)sulfanyl]pyrimidine (LS-17), and polysuccinimide, inhibit the growth of murine solid tumors by 70–95% and are recommended for further thorough preclinical studies of their antitumor properties and mechanisms of action.

An antinitrosative system as a factor in malignant tumor resistance to the cytotoxic effect of nitrogen monoxide

Inhibition of growth of a transplanted solid tumor in BDF1 mice bearing Lewis lung carcinoma cells on days 1–5 and 7–11 after tumor transplantation was observed at daily intraperitoneal administration of an aqueous solution of binuclear form of dinitrosyl iron complexes with glutathione at a dose of 200 μmol/kg (relative to one Fe(NO)2 group in the complexes). Inhibition of tumor growth during the administration of complexes (for 11 days) was 70 and 85% when an iron complex: free glutathione ratio in solution was equal to 1: 1 and 1: 10, respectively. Accelerated tumor growth that was faster than in the control began after cessation of dinitrosyl iron complex administration. The selective accumulation of dinitrosyl iron complexes in the tumor, as well as the accumulation of nitrosyl complexes of heme proteins was detected by the EPR method. The latter were observed in the tumor and control animals. It is hypothesized that delayed tumor development during administration of the binuclear form of dinitrosyl iron complexes to mice is caused by inactivation of heme-containing proteins under the action of NO released from these complexes, which provides antinitrosative defenses produced in malignant tumors.

Cellular effects of the antitumor drug aurumacryl

The cellular effects of aurumacryl (a drug based on gold polyacrylate, which previously showed significant antitumor activity in vivo against solid tumors in mice) were studied in the model of the MCF7 stable cell line of human breast carcinoma. It was found that aurumacryl possesses cytotoxic and cytostatic effects on tumor cells. The dose-dependent cytotoxic effect of aurumacryl is expressed as the death of 60% of tumor cells after incubation with aurumacryl at a dose of 1 mg/mL for 24 h. The proliferation kinetics of the surviving fraction of tumor cells also undergoes significant changes, which is expressed in the predominant accumulation of the cells (93%) in the G0 phase of proliferative rest and in a significant decrease in the number of proliferating cells to 7%. These data could be interpreted as evidence of the loss of the reproductive ability of the surviving cells after treatment with aurumacryl.

The antitumor activity of the S-nitrosoglutathione and dinitrosyl iron complex with glutathione: Comparative studies

The antitumor activity of the binuclear form of dinitrosyl iron complexes with glutathione against Lewis lung carcinoma was found earlier with intraperitoneal administration of the complexes. This activity was also observed when this preparation was injected subcutaneously. The complex inhibited the tumor growth by 43% upon subcutaneous injection at a daily dose of 100 µM/kg (as calculated per one iron atom in the binuclear dinitrosyl iron complex) for 10 or 15 days. The effect was observed during the first 2 weeks after tumor transplantation. After this, the tumors began to grow at a rate that was equal to or even higher than that for the control animals. The mean survival time for the treated mice exceeded the control values by 30%. Binuclear dinitrosyl iron complexes were also effective against Ca-755 adenocarcinoma with intraperitoneal administration. In this case, however, the mean survival time for the treated animals only increased by 7%. It was also shown that S-nitrosoglutathione inhibited the growth of Lewis lung carcinoma and Ca-755 adenocarcinoma by 70 and 90%, respectively. However, in contrast to binuclear dinitrosyl iron complexes, the antitumor effect of S-nitrosoglutathione decreased with an increase in the daily dose of the compound from 200 to 400 µM/kg. The initial antitumor effect of binuclear dinitrosyl iron complexes and S-nitrosoglutathione is suggested to be due to NO that is released from both compounds. The subsequent suppression of the effect is caused by the activation of antinitrosative and antioxidant defense systems in tumors.

Experimental study of the antitumor effect of aurumacryl

Gold polyacrylate (aurumacryl) belonging to a new class of compounds for oncology — metal polyacrylates — was shown to exhibit strong antitumor activity. Aurumacryl causes 80—90% growth inhibition in vivo of murine solid tumors (Lewis lung carcinoma, Ca-755 adenocarcinoma, and Acatol adenocarcinoma) compared to the control and induces cell death in vitro in 60% of MCF-7 human breast carcinoma cells. Substantial changes in proliferation kinetics of the surviving fraction of tumor cells following treatment with aurumacryl were observed, which are related to the predominant accumulation (93%) of cells in the proliferative resting phase G0 and a substantial decrease in the percentage of proliferating cells (7%). These data provide evidence that the cells that survive lose reproductive ability under treatment with aurumacryl.

The antitumor effect of dinitrosyl iron complexes with glutathione in a murine solid-tumor model

A significant antitumor activity of aqueous solutions of binuclear dinitrosyl iron complexes with glutathione was found when they were injected intravenously in a model of a solid malignant tumor, that is, Lewis carcinoma, in mice. Dinitrosyl iron complexes completely inhibited the tumor growth (by 100%) at doses of 20, 10, and 2 μmol/kg in the first 11 days after the beginning of experiment followed by tumor proliferation at a rate that was lowest for the lowest of the used doses. At day 16, the inhibition of tumor growth was 90% when a solution of dinitrosyl iron complexes was injected at a dose of 2 μmol/kg five times with an interval of 2 to 3 days between injections; whereas the inhibition of tumor growth did not exceed 70 and 30% at doses of 10 and 20 μmol/kg, respectively. Acceleration, rather than inhibition of carcinoma growth was observed at a dose of 100 μmol/kg. The tumor weight increased 1.5–2.0 times compared to the control values, depending on the time.

Polysuccinimide: Experimental antitumor activity

The antitumor effect of a polymer of aspartic acid, polysuccinimide, against murine solid-tumor models, such as Lewis lung carcinoma, AKATOL adenocarcinoma, and Ca-755 adenocarcinoma was found. The tumor growth inhibition was 60–80% compared to the control. The antimetastatic activity of polysuccinimide was found; in the Lewis lung carcinoma model it manifests itself in inhibition of lung metastases by 60% compared to the control. It was shown that polysuccinimide does not shift the pH values of tumors (P-388 lympholytic leukemia, AKATOL adenocarcinoma) into the region of acidic values. The experimental study indicates the advisability of further profound preclinical trials of the antitumor properties and mechanism of action of polysuccinimide.